Abstract

3797

Introduction: In many human cancers, including prostate cancer, malignant transformation and disease progression are associated with changes in the choline containing phospholipids that can be visualized using magnetic resonance spectra (MRS). Using current MRI/MRS technologies, the choline resonance that can be measured in vivo appears a single peak in the proton spectral array. However, in vitro high resolution 31P and 1H analysis of tissue extracts reveals several compounds involved in phoshotidylcholine synthesis and hydrolysis, including choline, phosphocholine and glycerophosphocholine. Moreover, the specific ratios of choline metabolites that make up the in vivo choline peak are different in different cancers. Because certain non-malignant prostate lesions (including chronic prostatitis) may produce choline resonance in MRI/MRS studies, our objective is to determine which of the choline metabolic pathways are differentially up-regulated in organ confined prostate cancers. In this study, we evaluate the expression of choline kinase (the rate-limiting enzyme for new synthesis of choline containing phospholipids) in prostate cancers expressing the tumor markers hepsin and/or AMACR. Methods: Tumor and benign tissues from radical prostatectomy specimens were systematically sampled using 4x4 mm tissue print micropeels for RNA preparation (each sample consists of approx 2000 cells). Choline kinase, hepsin, and AMACR transcripts were analyzed using endpoint and quantitative reverse transcriptase PCR (rt-PCR). Fifty samples from 20 specimens were included in this study. In addition, gene expression data from published studies comparing prostate cancer and non-malignant prostate tissue were analyzed using the Oncomine data mining resource. Results: In micropeel samples from radical prostatectomy specimens, we found that the expression of choline kinase was highly co-localized with the expression of hepsin (Spearman r=0.826, two tailed P value <0.0001), but much less associated with AMACR expression (r=0.410, P=0.206). Analysis of published microarray gene expression data shows a similar association, with the up-regulation of choline kinase in prostate cancer more strongly correlated with hepsin than with AMACR overexpression. This is most evident in the microarray data of Luo et al. (Mol Carcinog 33: 25, 2002), which compares microdissected samples of prostate cancer and adjacent normal tissue. Conclusions: Increased choline kinase expression distinguishes prostate cancers that overexpress hepsin from other prostate lesions. Selective choline kinase inhibitors may be useful in MRI/MRS studies to distinguish choline resonance produced by tumors that have upregulated the phosphocholine biosynthesis pathway from lesions with other non-malignant changes in choline metabolism.